1. Field of the Invention
The present invention relates to azaindolylidene derivatives active as kinase inhibitors and, more in particular, it relates to substituted azaindolylidene derivatives, a process for their preparation, pharmaceutical compositions comprising them and their use as therapeutic agents, particularly in the treatment of diseases linked to abnormal cell growth, such as cancer, in a mammal, including a human.
2. Discussion of the Background
The over-expression of protein kinases (PKs) is the hallmark of numerous diseases. A large share of oncogenes and proto-oncogenes are involved in human cancers code for PKs. The enhanced activities of PKs are also implicated in many non-malignant diseases such as benign prostate hyperplasia, familial adenomatosis, polyposis, neuro-fibromatosis, psoriasis, vascular smooth cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis glomerulonephritis and post-surgical stenosis and restenosis.
PKs are also implicated in inflammatory conditions and in the multiplication of viruses and parasites. PKs may also play a major role in the pathogenesis and development of neurodegenerative disorders.
For a general reference to PKs malfunctioning or disregulation, See, for instance, Current Opinion in Chemical Biology 1999, 3, 459-465.
Several azaindoles and analogues thereof are known in the art, even as therapeutic agents.
As an example, azaindole derivatives possessing cell cycle dependent kinase activity have been described in WO01/98299 to Pevarello et al., vinylene-azaindole derivatives and azaindolylidene derivatives have been described for use as tyrosine kinase inhibitors, respectively in WO94/14808 and in WO96/00226 to Buzzetti et al., while antiangiogenic bicyclic derivatives are claimed by Hennequin et al. in WO02/16348.
Azaindoles as kinase inhibitors are also presented in WO03/000688 by P. Cox et al., and preparation of indoles and azaindoles as tachykinin antagonists is reported by Dinnell et al. in US2002/0022624, claiming activity against depression, anxiety, pain, inflammation.
Azaindole-Oxazolone derivatives and their use as anti-(Helicobacter pylori) agents are shown in PCT Int. Appl. WO 9749703 (Kanamaru et al.), preparation of azaidole-pyrazolinones as inhibitors of serine/threonine and tyrosine kinase activity is reported by Moset, M. et al. in PCT Int. Appl. WO 2001009121, the synthesis of azaindoles by Bishop, B. et al. in UK Pat. Appl. GB 2298199, while the use of new and known pyrrolo-pyridine derivatives as selective dopamine D4 receptor subtype antagonists—useful in treatment of psychotic disorders and alleviating symptoms of schizophrenia, without side-effects of classical neuroleptic drugs is described to Kulagowski, J. et al. in GB 2298198.
New 2-pyrazin-5-ones are serine/threonine and tyrosine kinase inhibitors, useful for treating e.g. cancer, hyperproliferative disorders, angiogenesis, inflammatory diseases and vascular hyperpermeability by Arnold, L. D. et al. in WO 2001009121.